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Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma.

ABSTRACT: Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities.

SUBMITTER: Ortiz-Ruiz A

PROVIDER: S-EPMC8037116 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma.

Ortiz-Ruiz Alejandra A Ruiz-Heredia Yanira Y Morales María Luz ML Aguilar-Garrido Pedro P García-Ortiz Almudena A Valeri Antonio A Bárcena Carmen C García-Martin Rosa María RM Garrido Vanesa V Moreno Laura L Gimenez Alicia A Navarro-Aguadero Miguel Ángel MÁ Velasco-Estevez María M Lospitao Eva E Cedena María Teresa MT Barrio Santiago S Martínez-López Joaquín J Linares María M Gallardo Miguel M

Cancers 20210401 7

Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitoch ...[more]

PMID: 33916196

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Project description:IntroductionMyocardial damage is a mostly incurable complication of multiple myeloma (MM) that seriously affects the treatment outcome and quality of life of patients. Exosomal circular RNAs (exo-circRNAs) play an important role in tumor occurrence and development and are considered key factors in MM pathogenesis. However, the role and mechanism of action of exo-circRNAs in MM-related myocardial damage are still unclear. This study aimed to investigate correlations between exo-circRNAs and MM and to preliminarily explore the role of exo-circRNAs in MM-related myocardial damage.MethodsSix MM patients and five healthy controls (HCs) were included in the study. High-throughput sequencing and qRT-PCR verification were used to obtain a profile of abnormally expressed exo-circRNAs. GO, KEGG, miRanda, TargetScan and Metascape were used for bioinformatics analyses. H9C2 cells treated with exosomes from U266 cells were used in cell experiments. CCK-8, PCR, immunofluorescence and western blotting assays were used to detect cell proliferation and expression of autophagy-related indicators. Electron microscopy was used to observe the number of autophagic vesicles.ResultsBioinformatics analysis showed that circRNAs with upregulated expression had the potential to promote MM-related myocardial damage. In addition, PCR results confirmed that circ-G042080 was abundantly expressed in the serum exosomes of 20 MM patients. Correlation analysis showed that the expression level of circ-G042080 was positively correlated with the clinical level of MM and MM-related myocardial damage and that circ-G042080 might interfere with MM-related myocardial damage through a downstream miRNA/TLR4 axis. Cell experiments demonstrated that the circ-G042080/hsa-miR-4268/TLR4 axis might exist in H9C2 cells incubated with exosomes and cause abnormal autophagy.ConclusionAbnormal expression of serum exo-circRNAs was found to be associated with MM-related myocardial damage, suggesting that exo-circRNAs might become a new diagnostic marker of MM-related myocardial damage and a therapeutic target.

Dataset Information

Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma.

Publications

Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma.

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